From The Kidney Health Research Collaborative at University of California San Francisco and San Francisco VA Medical Center (C.A.P., R.S., M.S.); University of Alabama at Birmingham (L.A.M.); Oregon State University, Corvallis (M.C.O.); University of Texas Health Science Center at San Antonio (C.L.W., P.P.); and University of British Columbia, Vancouver, Canada (O.B.).

From The Kidney Health Research Collaborative at University of California San Francisco and San Francisco VA Medical Center (C.A.P., R.S., M.S.); University of Alabama at Birmingham (L.A.M.); Oregon State University, Corvallis (M.C.O.); University of Texas Health Science Center at San Antonio (C.L.W., P.P.); and University of British Columbia, Vancouver, Canada (O.B.).

From The Kidney Health Research Collaborative at University of California San Francisco and San Francisco VA Medical Center (C.A.P., R.S., M.S.); University of Alabama at Birmingham (L.A.M.); Oregon State University, Corvallis (M.C.O.); University of Texas Health Science Center at San Antonio (C.L.W., P.P.); and University of British Columbia, Vancouver, Canada (O.B.).

From The Kidney Health Research Collaborative at University of California San Francisco and San Francisco VA Medical Center (C.A.P., R.S., M.S.); University of Alabama at Birmingham (L.A.M.); Oregon State University, Corvallis (M.C.O.); University of Texas Health Science Center at San Antonio (C.L.W., P.P.); and University of British Columbia, Vancouver, Canada (O.B.).

From The Kidney Health Research Collaborative at University of California San Francisco and San Francisco VA Medical Center (C.A.P., R.S., M.S.); University of Alabama at Birmingham (L.A.M.); Oregon State University, Corvallis (M.C.O.); University of Texas Health Science Center at San Antonio (C.L.W., P.P.); and University of British Columbia, Vancouver, Canada (O.B.).

From The Kidney Health Research Collaborative at University of California San Francisco and San Francisco VA Medical Center (C.A.P., R.S., M.S.); University of Alabama at Birmingham (L.A.M.); Oregon State University, Corvallis (M.C.O.); University of Texas Health Science Center at San Antonio (C.L.W., P.P.); and University of British Columbia, Vancouver, Canada (O.B.).

From The Kidney Health Research Collaborative at University of California San Francisco and San Francisco VA Medical Center (C.A.P., R.S., M.S.); University of Alabama at Birmingham (L.A.M.); Oregon State University, Corvallis (M.C.O.); University of Texas Health Science Center at San Antonio (C.L.W., P.P.); and University of British Columbia, Vancouver, Canada (O.B.).

From The Kidney Health Research Collaborative at University of California San Francisco and San Francisco VA Medical Center (C.A.P., R.S., M.S.); University of Alabama at Birmingham (L.A.M.); Oregon State University, Corvallis (M.C.O.); University of Texas Health Science Center at San Antonio (C.L.W., P.P.); and University of British Columbia, Vancouver, Canada (O.B.).

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In Response:

We thank Dr Mezue and colleagues for their interest in our work. We agree that understanding the mechanisms to explain the differential associations of rapid decline with cardiovascular outcomes in the higher- versus lower-target blood pressure (BP) arms in SPS3 (Secondary Prevention of Small Subcortical Strokes) is important.1 The authors pose the hypothesis that differences in proteinuria levels over time may explain these observed differences. Although this remains a possibility, we are unable to make robust evidence-based conclusions with the current data because SPS3 did not include systematic measures of proteinuria over time. However, we believe that proteinuria is unlikely to be the missing piece to explain our findings. First, the levels of proteinuria are likely to be randomly distributed in both arms, and of a similar magnitude at baseline. Second, we do not expect the SPS3 population to have a high prevalence of severe proteinuria because participants had a relatively low prevalence of diabetes mellitus and, unlike CRIC (Chronic Renal Insufficiency Cohort),2 SPS3 was not enriched for kidney disease. In addition, the use of inhibitors of the renin angiotensin system (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) was very high in both groups throughout the study. As presented, >67% of persons were actively using these medications at baseline. In the intensive arm, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, calcium channel blockers, and diuretics all increased in similar proportions. Few persons in SPS3 were never on an angiotensin-converting enzyme inhibitors/angiotensin receptor blockers.

As the authors suggest, we believe that our findings outline an important opportunity for future research. SPRINT (Systolic Blood Pressure Intervention Trial) also reported higher rates of renal function decline among persons with no established chronic kidney disease treated to targets <120 mm Hg, compared with a higher BP target.3 We look forward to data from SPRINT, which may help clarify whether this represents a hemodynamic change versus kidney injury. Specifically, the current available data highlight an opportunity to measure novel biomarkers of kidney injury to understand the extent of injury to different parts of the nephron with aggressive BP lowering. If results of SPRINT and SPS3 result in modification of BP guidelines, nephrologists need to be prepared to address declining estimated glomerular filtration rates in hypertensive persons being treated to lower BP targets.